The OBR Blog

The 2017 Genitourinary Cancers Symposium takes place in Orlando, FL, on February 16 – 18, and a press cast held in advance of the meeting featured 3 important abstracts, with these key findings:

For patients with metastatic renal cell carcinoma, response to immunotherapy — specifically anti-PD-1/PD-L1 agents — may remain durable even if the drugs are discontinued early due to side effects

Also in patients with metastatic renal cell cancer, receipt of antibiotics within 1 month of starting immunotherapy may render checkpoint inhibitors less effective

Liquid biopsy in patients with advanced prostate cancer can reveal multiple genetic alterations in cell-free circulating tumor DNA (ctDNA) — this approach is simpler than traditional tissue biopsy and could identify new treatment targets for patients whose disease is progressing

Early Discontinuation of PD-1/PD-L1 Blockers May Not Compromise Efficacy

In a small study of 19 patients with metastatic renal cell carcinoma (RCC), discontinuation of anti-PD-1/PD-L1 immune checkpoint inhibitors due to side effects did not always lead to poor outcomes. The findings may challenge the current practice of continuing these drugs until (and sometimes after) the patient’s disease progresses.

Among 19 patients who initially responded to nivolumab but discontinued because of immune-related side effects, 42% had a durable response lasting for 6 months or longer, according to Rana R. McKay, MD, of the University of California San Diego School of Medicine.

“In medicine, we are constantly balancing the benefits and risks of any given treatment. This is a small study, and our findings need to be validated in a larger group of patients, but it underscores that in some cases, immunotherapy can have lasting benefits even after treatment discontinuation,” she said.

Two thirds of patients had received nivolumab as a single agent and the remainder received it in combination with other systemic treatments. The median time on immunotherapy was 5.5 months. All 19 discontinued treatment because of immune-related side effects, such as joint pain, rash, eye problems, diarrhea, and inflammation of the pituitary gland, muscle, heart, liver, pancreas, kidney or lung. Steroids were administered to 84% of patients and additional immunosuppressive agents were required for 11%. More than half the group had ongoing toxicity at the time of the analysis.

In 3 (16%) patients, the tumor progressed immediately after stopping treatment, but 8 (42%) patients had a continued response after being off treatment for at least 6 months. The remaining 8 (42%) were off treatment for 4 to 6 months or had follow-up for less than 6 months. The durable responders spent a median of 11 months on treatment and 20 months off treatment, reported Dr. McKay.

The prospective OMINIVORE study (Phase 2 study of Optimized Management of NIVOlumab based on Response) will further explore the efficacy of immunotherapy treatment discontinuation in treatment responders.

Press cast moderator and ASCO Expert Sumanta Pal, MD, reiterated the study’s message: that while the “unintended consequences of a reinvigorated immune response,” ie, immune-related adverse events, can be “serious,” patients with these side effects “can still have tangible benefit from these drugs.”

Recent Antibiotic Use May Negate Immunotherapy Benefits

In a retrospective analysis, patients with metastatic RCC who were treated with antibiotics within 1 month of starting treatment with immune checkpoint inhibitors had a significantly shorter progression-free survival, versus patients not taking antibiotics, according to French investigators.

The researchers attribute this to the ability of antibiotics to wipe out “good bacteria” in the gut, based on preclinical studies showing that certain microorganisms in the gut interact with the immune system in a way that facilitates the effect of immune checkpoint inhibitors.

The study is the first to analyze the impact of antibiotics on immune checkpoint inhibitors, and provides the first evidence of a relationship between the gut microbiome and patients’ response to immunotherapy.

The study included 80 patients with metastatic RCC enrolled in a trial of anti-PD-1/PD-L1 agents. Of these, 16 (20%) had been treated with broad-spectrum antibiotics (mostly beta-lactamases and fluoroquinolones) from baseline up to 1 month prior to the first injection.

This statistical association was maintained in a multivariate analysis that adjusted for age, gender, disease risk group, tumor burden and use of proton pump inhibitors. Antibiotic users’ risk for progression was increased more than four-fold vs non-users.

“Although it’s too early to conclude about overall survival, with median follow up of less than 6 months, there is already a negative trend in the antibody-positive group,” reported Lisa Derosa, MD, MD, a PhD candidate at the Gustave Roussy Cancer Institute, Paris-Sud University in Villejuif, France.

Dr. Derosa suggested that the findings may be applicable to other tumor types, since antibiotics are frequently used in cancer patients in general to prevent and treat treatment-related infections. At this time, she does not recommend withholding antibiotics from patients taking checkpoint inhibitors.

Dr. Pal agreed, stating, “While Dr. Derosa’s findings are very intriguing, they were retrospectively generated and therefore are hypothesis-generating. Having said that, the observations are consistent with preclinical observations. With further prospective validation, we may gain insight as to whether the bacterial composition of the gut affects clinical outcomes, and this could help guide us in our antibiotic usage. Meanwhile, we must consider that antibiotics are used under circumstances that are medically necessary.”

Analysis of cancer DNA from blood samples is yielding some new leads for potential prostate cancer treatment targets. With a commercially available liquid biopsy — which examines cell-free circulating tumor DNA (ctNDA) in the bloodstream — researchers identified new genetic mutations in prostate cancers, some of which were associated with poor prognosis.

Cell-free DNA reveals a tumor’s genetic profile, for which targeted treatments can be designed. The genetic landscape, however, changes over time, rendering some drugs ineffective because resistance develops.

If the ctDNA can identify the evolving mutations, clinicians could discontinue futile treatments and switch therapies, explained Guru Sonpavde, MD, of the University of Alabama in Birmingham.

In 163 patients, researchers explored associations between DNA changes and clinical outcomes, and in 64 patients they documented genetic changes over time through serial testing.

“Almost all the patients (94%) had some change detected, and most changes were associated with worse poor outcomes,” reported Dr. Sonpavde.

Higher number of ctDNA alterations was associated with shorter time to treatment failure (P=0.026). Patients with prior treatment for mCRPC had significantly more alterations in the androgen receptor gene (AR) than untreated patients (56% vs 37%; P=0.028).

Genes most often mutated were TP53, AR, APC, and NF1. Increased copy numbers were most common with AR, MYC and BRAF; increased cancer gene copy number can lead to proliferation of proteins that drive tumor growth.

Serial testing revealed that changes in AR over time were common. Importantly, patients with these mutations also trended toward shorter remissions (P=0.053) and shorter survival time (P=0.09).

The findings via ctDNA were consistent with changes observed through traditional tissue biopsy, suggesting that noninvasive liquid biopsy may be a viable alternative. While there are currently no approved drugs targeting the most common mutations observed, some are in clinical trials noted investigators.

Dr. Sonpavde acknowledged that a controlled, prospective clinical trial is needed to confirm that treatment based on the molecular information from ctDNA improves patient outcomes.

Dr. Pal remarked that the study offers “one of the largest clinically annotated datasets describing features of ctDNA in advanced prostate cancer, which is a simple and convenient way to assess DNA composition and can reveal new mutations that clinicians can use to personalize therapy… The development of new agents targeting the androgen receptor is a good future direction of research.”